This is an application for a Senior Scientist K05 award for the research career development of Dr. Charles Chavkin who is the Allan and Phyllis Treuer Chair of Pain Research in the Department of Pharmacology at the University of Washington. Dr. Chavkin received his PhD training in pharmacology at Stanford University, completed postdoctoral training at the Salk Institute and Scripps Clinic before joining the faculty at the University of Washington. He is currently the principal investigator of RO1-DA11672-06, R01-DA16898-02, P01-DA15916-03, and director of T32-DA07278-11. The research aims of these grants are respectively designed to 1) study the phosphorylation mechanisms regulating of opioid receptor activation of Kir3 type potassium channels, 2) study the cellular mechanisms responsible for behavioral stress-induced potentiation of the cocaine reward, 3) study the mechanisms of opioid analgesic tolerance using transgenic mouse models, and 4) supervise training of predoctoral and postdoctoral fellows in molecular approaches of drug abuse research. The purpose of this K05 application is to consolidate salary support for Dr. Chavkin and to reduce his non-research related administrative responsibilities. This plan has the full support of the department of pharmacology Chair and the Vice-Dean for Research in the School of Medicine. The long term goals of the proposed research plan are to further develop a multidisciplinary approach to the study of the actions of endogenous dynorphin opioid neuropeptides in drug addiction. The dynorphin/kappa opioid system seems to function as key mediators of the response to chronic stress in ways that potentiate the rewarding properties of cocaine. Understanding how chronic stress increases the risk of drug addiction and increases the risk of relapse has important therapeutic implications. The multidisciplinary approach necessary to address these questions requires molecular biological tools to define the targets of drug action, molecular pharmacological methods to resolve the cellular events underlying the responses, electrophysiological methods to define the actions of drugs on the neurons affected, anatomical methods to define the neural circuits and sites of drug action, and behavioral methods to provide relevant and valid stimuli to the nervous system. The award would greatly strengthen the candidate's ability to provide leadership in this integrative effort.